A major pathological hallmark of Alzheimer's disease (AD) is the abundance of deposits, called neuritic plaques, in key areas of the brain that control memory and cognition. These neuritic plaques are largely comprised of aggregations of fibrillar peptides referred to as amyloid β (Aβ) peptides. The longest of these Aβ peptides, designated Aβ42, is the most prone to aggregate into plaques that ultimately interfere with the neuronal connectivity at synapses within the brain. Individuals genetically predisposed to early-onset forms of AD invariably make a greater proportion of the longer Aβ peptides, especially Aβ42, relative to unaffected individuals. Aβ peptides, including the pathogenic Aβ42 peptide, are derived via proteolysis from a much larger precursor molecule known as the amyloid β precursor protein (APP).
During normal catabolism, two crucial enzymes, or proteases, are responsible for generating these Aβ peptides from APP. The first enzyme, beta-secretase (β-secretase), cuts the APP molecule into two major pieces comprised of an extracellular fragment and a membrane-associated fragment. The second enzyme, gamma-secretase (γ-secretase), then cleaves the membrane-associated fragment into one of several different forms of Aβ peptide. Gamma-secretase is currently understood to be a membrane complex of at least four proteins: presenilin (PS-1 or PS-2), nicastrin, Aph-1, and Pen-2. Activation of γ-secretase requires that PS-1 is endoproteolyzed into two fragments, each of which is believed to contribute one aspartate to the active site of the aspartyl protease activity.
Substantial efforts have been devoted to developing drugs that lower Aβ peptide levels by inhibiting gamma-secretase activity. However, these gamma-secretase inhibitors (GSIs) have been associated with gastrointestinal side effects, probably because they interfere with other necessary functions of gamma-secretase such as Notch proteolytic processing (e.g., LY-450,139) resulting in goblet cell hyperplasia. Indeed, a number of these GSI's have been shown to directly interact with PS-1.
Recently, a series of gamma-secretase modulatory compounds have been identified that modulate the enzyme's activity towards APP without preventing it from performing its other normal functions (e.g., Notch proteolysis, E-cadherin proteolysis). These compounds, referred to as gamma-secretase modulators (GSMs), are predicted to overcome some of the pitfalls associated with the GSI compounds. As such, these GSMs may be improved therapeutics. These GSM's are distinct from the far less potent substrate binding, NSAID (non-steroidal anti-inflammatory drug)-like GSM's described by Weggen S. et al. “A subset of NSAIDS lower amyloidogenic Aβ42 independently of cyclooxygenase activity” in Nature (2001) 414: 212-216.
However, the molecular target of gamma-secretase modulators is as yet unknown. Identification of the molecular target of GSMs would facilitate development of improved treatments for AD (and related indications) and provide approaches to screen for, and identify, new GSMs that can be used to prevent or treat AD and other diseases associated with pathogenic deposits of Aβ.